Method of introducing a malonyl radical in delta-position to a carbonyl radical in steroids and 1, 2, 3, 4, 7, 8, 9, 10-11, 12, 13, 14, 16, 17-tetrahydro-15h-cyclopenta[alpha]-phenanthren-7-one-3-malonates produced thereby



Patented Aug. 17, 1954 METHOD OF INTRODUCING A MALONYL RADICAL IN B-POSITION TO A CARBONYL RADICAL IN STER OIDS AND 1,2,3,4,7,8,9,10-

'II,12,13,14,16,17 -TETRAHYDRO- HIE-CYCLO- PENTAEa] PHENANTHREN 7 ONE 3 IHALONATES PRODUCED THEREBY Jack W. Rails, Morton Grove, IlL, assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application March 20, 1952, Serial No. 277,733

The present invention relates to a method of introducing a malonyl radical in ISHDOSIIJIOII to a carbonyl radical and, more particularly, to the addition of a metallo derivative of a lower aliphatic type of ester ofmalonic acid, to an fin/,5- di-unsaturated ketone and the products produced thereby.

The over all process and the probable intermediates formed therein can be represented In thisformula M is an alkali metal radical, R is a lower aliphatic radical, and R, R" and R' are parts of an otherwise saturated bicyclic fused ring system and, particularly, parts of a hexahydronaphthalene ring. Of special interest are systems in which this hexahydronaphthalene ring is a part of a polyhydrocyclopenta[alphenanthrene nucleus. In that case the over all re action can be represented as follows:

M being an alkali metal atom such as lithium, sodium and potassium and B being a lower alkyl radical such as methyl, ethyLpropyl or a lower phenylalkyl radical such as benzyl andphenethyl.

Of special pharmaceutical utility, particularly inthe production of steroidal hormonal effects and of hydrocholeresis, arethe lower aliphatic 8 Claims. (Cl. 260--397.1)

esters of 7-oXo-10,13-dimethyl-(l,2,3,4,'7,8,9,l0,-

11,12,l3,14,16,17 tetradecahydro 151i) cyclopenta[alphenanthrene-3-malonic acids carrying, as additional substituents attached to the 17-position, a lower alkyl or acyl radical.

The condensation reaction is conducted conveniently by heating under anhydrous conditions of a solution of a lower alkali metal. alkoxide, preferably a methoxide or ethoxide, in a lower alkanol with the malonate and a substantial equivalent of a 1,2,7,8,9,10,11,12,13,14,16,17-do decahydro 15I I cyclopenta[alphenanthren-7- one. The sodium salt is then treated with dilute aqueous acid and the ketonic product extracted with an organicsolvent. Purification by chromatographic methods, using such adsorbents as silica gel has been found useful.

The esters can be dealkylated in the conventional manner using alkali. The resulting 7- OXo 1,2,3,4,7,8,9,10,11,12,13,14,16,l7 tetradecahydro 15E cyclopenta[alphenanthrene 3- malonic acids are useful intermediates for the preparation of the hitherto unavailable 7-oxo- 1,2,3,4,7,8,9,10,11,12,13,14,16,17 tetraclecahydro- 15E cyclopentalalphenanthrene 3 acetic acids which are obtained by destructive distillation of the malonic acids with loss of carbon dioxide.

Derivatives useful in the identification of these esters of the 7-oxo-1,2,3,4,7,8,9,10,11,12,13,l4,l6, l7 tetradecahydro 15g cyclopenta[a]phenanthrene-3emalonic acids are the T-ethylene mercaptoles which are obtained by treatment of the malonate with an aryl sulfonic acid and then with ethanedithiol.

The following experimental part describes in detail the manner of conducting the process of this invention. However, it is not to be construed as limited in spirit or in scope by the ex perimental details presented since it will be apparent to those skilled in the art that many modifications in materials and methods may be practiced without departing from the invention. Temperatures are given in degrees centigrade (3.), relative amounts of materials in parts by weight, and pressures in millimeters (mm) of mercury.

EXAMPLE 1 Diethyl ester of 7o.rocholesteryl-3-malonic acid To a solution of sodium ethoxide in ethanol prepared from 460 parts. of sodium and 7000 parts of ethanol, there is added a solution of 3210 parts of diethyl malonate and 7640 parts of 3,5-cholestadien-7-one (cf. Stavely and Bergmann, Journal of Organic Chemistry, volume 1, pages 567 and 575: 1936) in 10,000 parts of ethanol. The mixture is heated under reflux in a nitrogen atmosphere for 90 minutes and, after standing at room temperature for 48 hours, the reaction mixture is poured into 30,000 parts of water containing 2000 parts of acetic acid. The product is extracted with chloroform and the extract is washed with water, dilute sodium bicarbonate solution and again with water. The chloroform solution is then dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated. The resulting mixture is readily separated chromatographically, using silica gel as the adsorbent. The ethyl 7-oxocholesteryl-3- malonate crystallizes from 95% ethanol in small needles melting at about l06107 C. It has the structural formula CH3 CH3 (17H (CH2)?! CHa-CH O2H5OOC CH- O C2H OOO EXAMPLE 2 Diethy-Z ester of 7-orochoZesteryZ-3-malonic acid 7-ethylene mercaptole A solution of 5'70 parts of the diethyl ester of 7-oxocholesteryl-3-malonic acid and 250 parts of p-toluene sulfonic acid monohydrate in 5000 parts of acetic acid is treated at room temperature by addition of 200 parts of ethanedithiol. After a few minutes a crystalline precipitate forms which is collected on a filter, washed with methanol and dried. The diethyl ester of '7- oxocholesteryl-3-malonic acid 'l-ethylene mercaptole melts at about l69-17l C. and has the structural formula CH(CH3)2 EXAMPLE 3 7-0xocholesteryl-3-malonic acid To a solution of 1000 parts of potassium hy droxide in 5000 parts of water and 15,000 parts of methanol, 470 parts of the diethyl ester of 7-oxocholesteryl-3-malonic acid are added. The mixture is heated under reflux for one hour in a nitrogen atmosphere, cooled and treated with ether and water. The ether layer is separated and extracted with water and the aqueous solutions are combined; this ether layer, after drying and evaporation, yields 3,5-cholestadien-7- one. The basic aqueous solution is cooled in an ice bath and acidified with 6-l l sulfuric acid whereupon the 7-oxocholesteryl-3-malonic acid precipitates. The precipitate is collected on a filter and crystallized from a mixture of acetic acid and water. Pale yellow crystals are obtained which melt at about 192 C. with evolution of carbon dioxide.

EXAMPLE 4 7-oxocholesteryZ-B-acetic acid omens I CH3 H CH3 CH3 I claim: 1. The process of preparing a compound of the structural formula R/ CH3 ROOC on o ROOO wherein R is a member of the class consisting of lower alkyl and lower phenylalkyl radicals and R. is a lower alkyl radical which comprises heating, under anhydrous conditions, of a metallomalonate of the structural formula wherein R is defined as hereinabove and M is an alkali metal atom with a substantial equivalent of a 1, 2, 7, 8, 9, 10, l1, 12, 13, 14, 16, 17-dodecahydro- 15E-cyclopenta a] -phenanthren-7-one.

2. The process of preparing a compound of the structural formula lower alkyl CH;

lower alkyl-O O C CH O lower alkyl-O O C v which comprises heating of an anhydrous alcoholic solution of a lower alkoxide of an alkali metal and a lower ,alkyl ester of malonic acid with a substantial equivalent of a 10, 13-dimethwherein R is a member of the class consisting of yl-l'I-lower alkyl-l, 2, 7, 8, 9, 10, 11, l2, 13, 14, lower alkyl and lower phenylalkyl radicals and R 16,17 dodecahydro 15E cyclopentaEalpheis a lower alkyl.

anth 6. A compound of the structural formula 3. The process of preparing a compound of the structural formula lower alkyl CH3 CH3 lower alkyl CH1 lower alkyl-O O C a CH 0 alkyl'o O o lower alkyl-O o 0 7. A compound of the structural formula lower alkyl-O O C CHwHm which comprises heating of an anhydrous alco- H2) holic solution of sodium and a lower dialkyl ester 3 of malonic acid with a. substantial equivalent of 0111-011 a 10,13-dimethyl-17-lower alkyl-1,2,'7,8,9,10,11,12, 0H, 13,14,161? dodecahydro 15 I I cyclopenta[alphenanthren-7-one.

4. The process of preparing a. compound of the structural formula CHwHm lower alkyl-O O 0 (CH2): CH 0 CH8 CH lower alkyl-O O C OH on, so 8. A compound of the structural formula GH:CH lower alkyl-O O C CHa OH:

CH- o lower alkyl-O O C a which comprises heating of an anhydrous alco- 4O holic solution of sodium and a lower dialkyl ester 5 0 0 of malonic acid with a substantial equivalent of a. CH 0 10,13 dimethyl l'l-(u-methylisoheptyl) -l,2,7,8, C H 0 O C 9,1o,11,12,13,14,1c,17 dodecahydro 15g cyclopenta[a]phenanthren-7-one. References Cited in the file of this patent 5. A compound of the structural formula UNITED STATES PATENTS Number Name Date 2,592,036 Kaiser Apr. 8. 1952 OH O 

7. A COMPOUND OF THE STRUCTURAL FORMULA 